| Asthma is a common disease, its pathogenesis is still unclear. Worldwide, about3million people suffer from asthma, with an incidence ranged from1%-18%in different countries. Severe asthma patients account for5%of all asthma patients. Asthma has become the world’s second largest deaths disease after cancer and disabling, and in China there are about25million asthma patients. steroids have good treatment effect for ordinary asthma but not for severe asthma. In ordinary asthma TH2cells are dominant, but in severe asthma there are more TH17in phlegm of patients, and the observed neutrophilia inflammation may be induced by IL-17produced fromTH17cells, which induced IL-8release from airway epithelial cells.. This raises the question:what is the function of TH17in severe asthma patients? A better understanding of the role played by Th17in severe asthma may be helpful in identifying new target for severe asthma treatment..Ordinary asthma is the airway chronic inflammation caused by eosinophils, mast cells and T lymphocytes and many kinds of inflammatory cells etc. This inflammation make susceptible persons with airway responsieness for various stimulating factor, and can cause the airway to become narrower, clinical manifestations have symptoms with repeated relapsing panting, difficulty in breathing, bosom frowsty or cough. Its pathogenesis is still unclear.CD4+T effector lymphocytes are distinguished in different subsets on the basis of their patterns of cytokine secretion. These subsets are TH1,TH2and TH17. In ordinary asthom, it is considered that TH1/TH2imbalance is the cause of asthma, namely genetic background and environmental factors lead to respiratory system and immune system dysplastic (including T cell differentiation and complex immune process taking cell factor for environment). The decline of TH1activity can not restrain TH2, and the rise of TH2activity caues the occurrence of airway inflammatory response. Most patients with asthma are caused by external allergies factors, only a few of them are due to genetic factors and they often have more serious asthma illness. It was found in clinical study that patients with severe asthma contains more TH17cells in lung, and TH17mainly contribute to the inflammation. Asthma patients with smokers also have TH17cells and neutrophile inflammation. However, TH17as a driver function of neutrophile inflammation remains yet unclear.TH17cells produces IL-17and IL-17-F, mainly through activating and adjusting STAT3and RORgt by the transformation factor IL-23. IL-17and closely related IL17-F induce the release of CXCL1and CXCL8from epithelial cells in airway, which results in neutrophile inflammation. In addition, DCs may induce IL-23and IL-17under the bacterial infections, it plays an important role in asthma. However, The interaction among DCs, IL-23, TH17in severe asthma patients is still unclear.Just as recently pointed out by P. J. Barnes:"TH17mechanism as manipulating severe asthma neutrophils inflammation function is not quite clear, worths more research, understanding these mechanisms may lead to new therapies, so that further studies are needed to understand TH17role in severe asthma, it may be a new target as future treatments for severe asthma".It was found in another recent study that TH17/TH2cells found in allergic asthma are able to produce both IL-17and IL-4, and this is consistent with the observation that different clinical phenotypes can coexist in the same patient. This brought forth the new questions:What is TH17, TH2function in patients with severe asthma? Since severe asthma contains more TH17, TH2, what is the relationshp among TH17and DCs? What is the specific mechanism that IL-23induces Th17lymphocyte subsets to secrete IL-17? How can we find key cell agents to adjust the balance between Th17and DCs, and to formulate effective treatment for severe asthma? Therefore, the function of TH17and TH2in severe asthma has become a top priorit in our study.Due to the high complexity of the interactions between innate and acquired immune cell in immune system, it is difficult to quantitatively describe the interaction between the cells of severe asthma using traditional biochemical and molecular biology method. The ABM method has promoted the research of immune response in various kinds of disease symptoms, including bacterial and viral infections, etc. The BIS platform by Virginia A Folcik is an effective tool to deal with the issue of complexity of biological systems. BIS is an ABM based simulation system to explore the interactions between the cells of the innate and adaptive immune system. The BIS simulates basic cell types, mediators and antibodies, and it consists of three virtual spaces representing parenchymal tissue, secondary lymphoid tissue and the lymphatic/humoral circulation. In this study, we use BIS to simulate three effects (immunity win,immunity loss and immunity hyper-response) of TH17models. and compare the simulation outcomes of TH17models with that of DCs models in the previous report. We explored possible propagation paths of severe asthma and the potential targets for severe asthma treatment, aiming at provding references for clinic cure of severe asthma.The BIS platform was implemented using REPAST software and JAVA language. By comparing TH17models with DCs models in BIS, we simulated the influence of TH17on actual immune system. We observed three kinds of immun effect (immune victory, immunity failure, immune hyper-response), to examine the role of TH17in severe asthma and the interaction caused by TH17between innate immune cells and acquired immune cells. In assocation with the clinical data, we discussed the potential function of TH17in severe asthma.TH17simulations:1. Taking DCs model as referrence, observing the three immune effects of TH17simulations by varing the initial cell numbers of TH17models.; 2. Under active conditions, taking DCs model as referrence, observing the three immune effects of TH17simulations by varing the initial TH17cell numbers of and adding cell numbers of other agent types(comparing with1);3. Under active conditions, taking DCs model as referrence, observing the three immune effects of TH17simulations by varing the initial TH17cell numbers and reducing cell numbers of other agent types (comparing with1)。 TH2Simulations:1. Taking DCs model as referrence, observing the three immune effects of TH2simulations by varing the initial cell numbers of TH2models.;2. Under active conditions, taking DCs model as referrence, observing the three immune effects of TH2simulations by varing the initial TH17cell numbers of and adding cell numbers of other agent types(comparing with1);3.Under active conditions, taking DCs model as referrence, observing the three immune effects of TH2simulations by varing the initial TH2cell numbers and reducing cell numbers of other agent types (comparing with1)。 Conclusions1. There are a little immune hyper-response change with TH17initial quantity, when TH17quantity increases, there are corresponding immune win probability and immune loss probability.2. Simulation results are consistent to the clinical experiment data.3. DCs are proliferating irritants of T Cells, and DCs in bacterial infections can induce IL-23, and IL-23can induce the TH17. It is likely that DCs/IL23/IL-17/neutral inflamation/severe asthma may be the path of generating severe asthma, and DCs apoptosis can end this cycle. The DCs apoptosis is an important mechanism to control the T-cell activation, which is consistent with experimental data.4. Smoking makes asthma illness heaver.(1) CS first delayed’endotoxin induction of cytokines’, such as IL-6reduced, curb inflammation, and later IL-8increased,which leds to severe asthma in respiratory airway.(2) IL-8mRNA level and LPs stimulating time are related, acting short time, produced IL-8level decreased and otherwise, acting longer time, produced IL-8level increased.(3) Oxide of cigarette smoke can stimulate the mature DC cells producing IL8cytokines, make asthma who smoke aggravate illness.5. There are a little immune hyper-response change with TH2initial quantity,when TH2quantity increases, there are corresponding immune win probability and immune loss probability.6. DCs are proliferating irritants, and DCs in action of special agents can induce TH2,predictably DCs/TH2/eosinophilic inflammation/severy asthma may be another path generating severe asthma. DCs apoptosis can end this cycle. The DCs apoptosis is an important mechanism to control the T-cell activation, which accords with experimental results.In summary, the BIS was used in this study to qualitatively examine the interactions of innate and adaptive immune cells in the immune response to a viral infection., and simulation outcomes were used to compare with the data reported in the previous study. The BIS simulations demonstrated that the degree of the initial innate response was a crucial determinant for an appropriate adaptive response. Excess in innate immunity resulted in excessive proliferation of adaptive immune cells. Deficiency in any of the immune system components increased the probability of failure to clear the viral infection. We used the ABM model to describe the interaction between innate immune cells and acquired immune cells of immune system and examined the role of TH17,TH2in severe asthma. To associate the simulation results with clinical data, we reached the conclusion that that TH17and DCs might be potential targets for severe asthma treatment, which can serve as reference for the clinical cure of severe athma.The novel contribution of this study are:1. It is the first time to use ABM method to examine the TH17role in severe athma. We explored TH17interaction with other immune cells in immune system. We associated our simulation results to the existing experimental data and clinical data, and quantitatively analysed the function of TH17in severe asthma. 2. As reported in recent studies, DCs in bacterial infections can induce IL-23, through adjustment for activating transformation factors RORrt and STAT3, IL-23can produce IL-17and IL17-F. IL-17and closely related IL-17F may induce the CXCL1and CXCL8release from the epithelial cells to attract neutrophile particles causing inflammation and result in neutrophile inflammation.. We used BIS platform, to simulate TH17interaction with other cells in immune system and compared TH17with DCs models. Our study suggested that DCs、TH17and severe asthma might be linked through the path:DCs/IL-23/TH17/neutrophile inflammation/severe asthma, and our simulation results are consistent to the clinical data, and this reinforce the presumption that TH17and DCs could serve as a new target for severe asthma treatment.3. Smoking makes asthma patients illness heaver, then, how do cigarette affect the immune system causing severe asthma? What is the molecular mechanism exposed by Cigarette? The paper quotes the experimental results illustrating above issues, namely, the CS initially delayed’endotoxin induction of cytokines’, such as IL-6reduced, curb inflammation, and later IL-8increase leading to respiratory severe asthma, IL-8mRNA level has related toLPs stimulating time, the less time for action,the less IL-8level produced, and vice, the longer time for action,the moreIL-8level produced, activated DCs in cigarette smoke make oxidants neutrophilic chemotactic factors (such as the number of IL-8) increased significantly, and antioxidant (NAC) in CSE and in cigarette smoke enhanced the PGE2and COX2secreted in mature DCs. These studies are very important because they illustrate cigarette smoke direct influence to activate complex DCs, and point out some pharmacological strategy, and effectively control chemotactic factors produced, actually could exacerbate prostaglandin production and increase the risk of lung cancer, which is identical of discussion TH17function in severe asthma based on TH17ABM.We can further do this study in the future in following aspects::1. Using BIS plaform to simulate time course TH17models between innate immune and acquire immune cells and study the three effects(immune win, immune loss, immune hyper-respond), and this will be helpful to further explore TH17function in severe asthma..2. Using BIS plaform to simulate time course TH2models, and study the three effects(immune win, immune loss, immune hyper-respond),3. take BIS as a pltform,simulate TH17model defending host preventing from Infection,so take TH17and other agent as target for treatment severe asthma,how to main its active side and control its negative function for arriving effect banlance need to further research.4. Further collecting the clinical and experimental data of TH17and TH2study, assocating these data with our sumulation models and working out the details of the propagation path leading to severe astham. |
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